trans-acetonide controlled endo-selective intramolecular nitrone-alkene cycloaddition of hept-6-enoses: A facile entry to calystegines, tropanes, and hydroxylated aminocycloheptanes

Article abstract of DOI:10.1021/ol062621o

(Chemical Equation Presented) High-yielding endo-selective intramolecular nitrone-alkene cycloaddition (INAC) reactions of hept-6-enoses controlled by a trans-acetonide to give bridged bicyclo[4.2.1]isoxazolidines exclusively are realized for the first ti

Full text of DOI:10.1021/ol062621o

ORGANIC
LETTERS
2007
Vol. 9, No. 2
207-209
trans-Acetonide Controlled
endo-Selective Intramolecular
Nitrone−Alkene Cycloaddition of
Hept-6-enoses: A Facile Entry to
Calystegines, Tropanes, and
Hydroxylated Aminocycloheptanes
Tony K. M. Shing,*,† Wai F. Wong,† Taketo Ikeno,‡ and Tohru Yamada*,‡
Department of Chemistry and Center of NoVel Functional Molecules, The Chinese
UniVersity of Hong Kong, Shatin, NT, Hong Kong, China, and Department of
Chemistry, Faculty of Science and Technology, Keio UniVersity, Hiyoshi, Kohoku-ku,
Yokohama, 223-8522, Japan
tonyshing@cuhk.edu.hk
Received October 25, 2006
ABSTRACT
High-yielding endo-selective intramolecular nitrone−alkene cycloaddition (INAC) reactions of hept-6-enoses controlled by a trans-acetonide to
give bridged bicyclo[4.2.1]isoxazolidines exclusively are realized for the first time. The cycloadducts were readily transformed into calystegine,
tropane, and hydroxylated aminocycloheptane frameworks.
Intramolecular nitrone-alkene cycloaddition (INAC) is a
versatile and important synthetic method for the preparation
of polyhydroxylated carbocycles from sugars.1 The exo or
the endo mode of INAC cyclization leads to a fused or a
bridged isoxazolidine, respectively (Scheme 1).2
There are only two examples3 of the formation of a bridged
bicyclo[4.2.1] system, i.e., a cycloheptane skeleton from
branched sugars, but many examples1 of unbranched hept-
6-enose derivatives give a fused bicyclo[4.3.0] system, i.e.,
a cyclohexane skeleton. However, the regio- and diastereo-
selectivity of these INAC reactions have not been rational-
ized.
The bridged bicyclo[4.2.1]isoxazolidine 1 is a versatile
synthetic intermediate because, upon hydrogenolysis of the
N-O bond, it provides the skeleton of aminocycloheptanol
Scheme 1. The Two Modes of INAC Cyclization
† The Chinese University of Hong Kong
‡ Keio University
(1) Koumbis, A. E.; Gallos, J. K. Curr. Org. Chem. 2003, 7, 585-628.
(2) Tufariello, J. J. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A.,
Ed.; Wiley: New York, 1984; Vol. 2, pp 83-168.
(3) (a) Roy, A.; Chakrabarty, K.; Dutta, P. K.; Bar, N. C.; Basu, N.;
Achari, B.; Mandal, S. B. J. Org. Chem. 1999, 64, 2304-2309. (b) Patra,
R.; Bar, N. C.; Roy, A.; Achari, B.; Ghoshal, N.; Mandal, S. B. Tetrahedron
1996, 52, 11265-11272.
10.1021/ol062621o CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/16/2006

2, proven to be a new class of glycosidase inhibitor.4
Synthetic manipulation of 2 could lead to alkaloid tropane
35 and calystegine 46 that exhibits specific glycosidase
inhibition7 (Scheme 2). Optically active tropanes are still in
Table 1. endo-Selective INAC Reactions of Hept-6-enoses
Scheme 2. Catalytic Hydrogenolysis of the N-O Bond in
Isoxazolidine 1 and Subsequent Transformation
demand for neuroscience research8 and the chemotherapeutic
use of glycosidase inhibitors as antitumor, antiviral, and
antidiabetic agents has been recognized.9 Thus stereocon-
trolled endo-selective INAC reactions of hept-6-enoses to
give bridged bicyclo[4.2.1]isoxazolidines are highly desir-
able. The present letter reports the use of trans-acetonide to
effect such regioselectivity for the first time and the facile
conversion of the cycloadducts into two calystegines 18 and
20, one tropane 22, and one hydroxylated aminocycloheptane
24.
Recently, we reported10 that exo-INAC cyclization was
the preferred pathway for hept-6-enoses containing a cis-
acetonide to give fused isoxazolidine exclusively whereas
hept-6-enoses with a 2,3-O-trans-diacetal gave a mixture of
fused (cyclohexane) and bridged (cycloheptane) isoxazo-
lidines. We reasoned that a more rigid diol blocking group
such as a trans-acetonide would favor the endo mode of
cyclization. Computational studies of INAC of debenzyl
D-lyxo-hept-6-enose 6 containing a 3,4-trans-acetonide show
that the endo-TS 5a (leading to a cycloheptane) is about 4.2
kcal mol-1 more stable than exo-TS 5b (leading to a cis-
fused cyclohexane).11 To our delight, treatment of 6, readily
available from D-ribose (vide infra), with N-methylhydroxyl-
amine in acetonitrile indeed afforded exclusively bridged
bicyclo[4.2.1]isoxazolidine 7 in excellent yield (Table 1).
The INAC should proceed through a chairlike TS with the
3,4-trans-diequatorial acetonide. We believed that efficient
overlap of bonding orbitals could only be feasible with
cycloheptane-endo-TS 5a that experiences less torsional
a For experimental details and X-ray crystallographic structures, see the
Supporting Information. b With N-methylhydroxylamine. c With N-benzyl-
hydroxylamine. d Not charaterized. e Overall isolated yield from the cor-
responding diol or alcohol.
strain than cyclohexane-exo-TS 5b, leading to exclusive
formation of 7. Furthermore, INAC of D-xylo-8, L-gluco-
11, and D-ido-14 hept-6-enoses all gave cycloheptanes
exclusively in excellent yields (Table 1). The stereochemistry
of the only or major heterocycle appears to be controlled by
the OR group at C-2. The new C-N bond is anti to the axial
OR-2 (entry 1) and syn to the equatorial OR-2 (entries 2-4).
With [4.2.1]isoxazolidines readily in hand, transformation
into the target molecules is straightforward (Scheme 3). For
example, deacetonation of 7 gave diol 16 that underwent
regioselective oxidation to give ketone 17. Hydrogenolysis
of the N-O bond and the benzylic C-O bond in 17
produced a calystegine B analogue 18. Debenzoylation of
12 or 15 followed by oxidation afforded ketone 19 that
yielded (S)-3-hydroxycalystegine B5 20 upon deprotection.
Toward tropane synthesis, cycloadduct 13 was debenzoylated
and then mesylated to give mesylate 21. Sequential acid
(4) Gravier-Pelletier, C.; Maton, W.; Dintinger, T.; Tellier, C.; Merrer,
Y. L. Tetrahedron 2003, 59, 8705-8720.
(5) For recent syntheses, see: (a) Zhang, Y.; Liebeskind, L. S. J. Am.
Chem. Soc. 2006, 128, 465-472. (b) Mans, D. M.; Pearson, W. H. Org.
Lett. 2004, 6, 3305-3308.
(6) For recent syntheses, see: (a) Skaanderup, P. R.; Madsen, R. J. Org.
Chem. 2003, 68, 2115-2122. (b) Marco-Contelles, J.; de Opazo, E. J. Org.
Chem. 2002, 67, 3705-3717.
(7) (a) Dra¨ger, B. Nat. Prod. Rep. 2004, 21, 211-223. (b) Asano, N.
Curr. Top. Med. Chem. 2003, 3, 471-484.
(8) Lounasmaa, M.; Tamminen, T. Alkaloids 1993, 44, 1-79.
(9) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J Tetrahe-
dron: Asymmetry 2000, 11, 1645-1680.
(10) Shing, T. K. M.; Wong, A. W. F.; Ikeno, T.; Yamada, T. J. Org.
Chem. 2006, 71, 3253-3263.
(11) For details, please refer to the Supporting Information.
208
Org. Lett., Vol. 9, No. 2, 2007

Scheme 3. Transformation of Cycloadducts 7, 12 or 15, and
Scheme 4. Syntheses of INAC Precursors
13
hydrolysis, N-O bond cleavage with concomitant nucleo-
philic displacement, and debenzylation of 21 produced
tropane 22. Synthesis of a hydroxylated aminocycloheptane
is also shown in Scheme 3 in which 13 was debenzoylated
to alcohol 23 that was hydrolyzed and then hydrogenolyzed
to give 24.
Preparation of INAC precursors is shown in Scheme 4.
Indium mediated aqueous allylation12 of D-ribose and D-
arabinose gave alkenes 25 and 27 which were readily
converted into aldehydes 6 and 8, respectively. Acetonation
of D-xylose afforded aldehyde 29,13 which immediately
underwent vinylation to give epimeric alcohols 30 and 31
in 28% and 18% respective overall yields. Both alcohols 30
and 31 were transformed readily into aldehydes 11 or 14,
respectively.
to give bridged bicyclo[4.2.1]isoxazolidines are realized for
the first time. This opens a facile synthetic avenue to optically
active calystegines, tropanes, and hydroxylated aminocyclo-
heptanes for biological evaluation.
Acknowledgment. This work was partially supported by
a CERG from Research Grants Council of HKSAR, China
(project no. 402805), and was also partially supported by a
Grant-in-Aid for the 21st century COE program “KEIO
LCC” from the Ministry of Education, Culture, Sports,
Science and Technology, Japan. The authors thank the
Research Center for Computational Science, Okazaki Na-
tional Institute, for their support of the DFT calculations.
Supporting Information Available: Additional informa-
tion, experimental procedures, and product characterization.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, high-yielding and exclusive endo-INAC
reactions of hept-6-enoses controlled by a trans-acetonide
(12) Prenner, R. H.; Schmid, B. W. Leibigs Ann. Chem. 1994, 73-78.
(13) Calinaud, P.; Gelas, J In PreparatiVe Carbohydrate Chemistry;
Hanessian, S., Ed.; Marcel Dekker, New York, 1997; pp 3-33.
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